Melanoma
Conditions
Keywords
Melanoma, OncoVEX^GM-CSF, GM-CSF, Stage IIIb, IIIc and IV Disease, oncolytic, OncoVex, T-Vec, talimogene laherparepvec
Brief summary
The objective of this study is to evaluate the efficacy and safety of treatment with talimogene laherparepvec compared to subcutaneously administered GM-CSF in patients with unresectable Stage IIIb, IIIc and Stage IV melanoma. The efficacy endpoints of the study aim to demonstrate overall clinical benefit for patients treated with talimogene laherparepvec as compared to GM-CSF.
Interventions
BIOLOGICALTalimogene laherparepvec
Up to 4 mL of 10⁸ pfu/mL/per intratumoral injection
BIOLOGICALGM-CSF
125 µg/m² subcutaneous injection
Sponsors
Amgen
BioVex Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males or females age ≥ 18 years * Stage IIIb, IIIc or stage IV disease that is not surgically resectable * Injectable disease (i.e. suitable for direct injection or through the use of ultrasound guidance) * At least 1 injectable cutaneous, subcutaneous or nodal melanoma lesion \>= 10 mm in longest diameter or, multiple injectable melanoma lesions which in aggregate have a longest diameter of \>= 10 mm * Serum lactate dehydrogenase (LDH) levels less than 1.5 x upper limit of normal (ULN) * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Prolongation in International Normalized Ratio (INR), Prothrombin Time (PT), and Partial Thromboplastin Time (PTT) when the result is from therapeutic anticoagulation treatment are permitted for patients whose injectable lesions are cutaneous and/or subcutaneous such that direct pressure could be applied in the event of excessive bleeding
Exclusion criteria
* Clinically active cerebral or any bone metastases. Patients with up to 3 (neurological performance status of 0) cerebral metastases may be enrolled, provided that all lesions have been adequately treated with stereotactic radiation therapy, craniotomy, gammaknife therapy, with no evidence of progression, and have not required steroids, for at least two (2) months prior to randomization * Greater than 3 visceral metastases (this does not include lung metastases or nodal metastases associated with visceral organs). For patients with \< 3 visceral metastases, no lesion \> 3 cm, and liver lesions must meet Response Evaluation Criteria In Solid Tumors (RECIST) criteria for stable disease for at least 1 month prior to randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Durable Response Rate | From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months. | Durable response rate was defined as the percentage of participants with a complete response (CR) or partial response (PR) maintained continuously for at least 6 months from the time the objective response was first observed and initiating within 12 months of starting therapy as assessed by the Endpoint Assessment Committee (EAC). This reflects all new sites of disease as well as disease sites identified at baseline. Disease assessments were performed at the beginning of each treatment cycle in accordance with modified World Health Organization criteria. CR: Disappearance of all clinical evidence of tumor (both measurable and non-measurable but evaluable disease); PR: ≥ 50% reduction in the sum of the products of the perpendicular diameters of all measurable tumors at the time of assessment as compared to baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months. | Objective response rate was defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) assessed by the Endpoint Assessment Committee (EAC). Best overall response for a patient is the best overall response observed across all time points. Disease assessments were performed at the beginning of each treatment cycle and assessed in accordance with modified World Health Organization criteria. CR: Disappearance of all clinical evidence of tumor (both measurable and non-measurable but evaluable disease); PR: ≥ 50% reduction in the sum of the products of the perpendicular diameters of all measurable tumors at the time of assessment as compared to baseline. |
| Duration of Response | From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months. | The duration of response is defined as the longest individual period from entering response (CR or PR as assessed by the EAC) to the first documented evidence of the patient no longer meeting the criteria for being in response or death, whichever is earlier. Responses were censored at the last assessment showing response. |
| Overall Survival | From randomization until the first 290 survival events had occurred (data cut-off date of 31 March 2014); median time on follow-up was 44 months. | Overall survival was defined as the time from the date of randomization to the date of death from any cause. Overall survival time was censored at the last date the patient was known to be alive when the confirmation of death was absent or unknown. Participants were censored at the date of randomization if no additional follow-up data were obtained. |
| Time to Treatment Failure | From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months. | Time to treatment failure was assessed by the investigator, and calculated from randomization until the first clinically relevant disease progression where there is no response achieved after the progression, or until death if no such progression occurs. Participants who did not have clinically relevant progression or did not die were censored at the time of the their last tumor assessment. Participants who withdrew from treatment due to a clinically unacceptable toxicity were not considered as an event in the analysis. Progressive disease (PD) is defined as a ≥ 25% increase in the sum of the products of the perpendicular diameters of all measurable tumors since baseline, or the unequivocal appearance of a new tumor since the last response assessment time point. Clinically relevant progressive disease is PD that is associated with a decline in performance status and/or in the opinion of the investigator the patient requires alternative therapy. |
| Response Interval | From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months. | Response interval is defined as the interval between the date of randomization and the date of the last documented evidence of response (CR or PR as assessed by the Investigator) prior to any new anti-cancer therapy. Response Interval post response onset was censored if a patient was still in response at the last observation. |
| Response Onset | From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months. | Response onset is defined as the time from the date of randomization to the date of the first documented evidence of response (CR or PR) per EAC assessment. |
Countries
Canada, South Africa, United Kingdom, United States
Participant flow
Recruitment details
Eligible patients were adults with histologically confirmed, not surgically resectable, stage IIIB - IV melanoma suitable for direct or ultrasound-guided injection. Among those randomized, the first patient enrolled 29 April 2009 and last patient enrolled 8 June 2011. 1 patient randomized 3 times is counted once under talimogene laherparepvec.
Pre-assignment details
Patients were assigned at a 2:1 ratio using central random assignment to receive intralesional talimogene laherparepvec or subcutaneous granulocyte macrophage colony-stimulating factor (GM-CSF). Randomization was stratified by site of first recurrence, presence of liver metastases, disease stage, and prior nonadjuvant systemic treatment.
Participants by arm
| Arm | Count |
|---|---|
| GM-CSF GM-CSF was administered at a dose of 125 μg/m²/day subcutaneously for 14 days in 28-day cycles for 24 weeks. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, or lack of response by 12 months, for a maximum of 18 months. | 141 |
| Talimogene Laherparepvec Participants received talimogene laherparepvec on Days 1 and 15 of each 28-day cycle for 24 weeks. The initial dose was at a concentration of 10⁶ PFU/mL, injected into 1 or more skin, subcutaneous or nodal tumors. Subsequent doses began at least 3 weeks after the first dose and consisted of talimogene laherparepvec at a concentration of 10⁸ PFU/mL. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, lack of response by 12 months, or disappearance of all injectable lesions, for a maximum of 18 months. | 296 |
| Total | 437 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 95 | 190 |
| Overall Study | Lost to Follow-up | 3 | 2 |
| Overall Study | Other | 1 | 2 |
| Overall Study | Withdrawal by Subject | 12 | 5 |
Baseline characteristics
| Characteristic | Total | Talimogene Laherparepvec | GM-CSF |
|---|---|---|---|
| Age, Continuous | 63.03 years STANDARD_DEVIATION 13.81 | 63.07 years STANDARD_DEVIATION 13.68 | 62.92 years STANDARD_DEVIATION 14.13 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 | 307 participants | 210 participants | 97 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 | 114 participants | 82 participants | 32 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Missing | 16 participants | 4 participants | 12 participants |
| Line of Therapy First Line | 203 participants | 138 participants | 65 participants |
| Line of Therapy Second Line or Greater | 234 participants | 158 participants | 76 participants |
| Race/Ethnicity, Customized Asian | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized Black | 3 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized Other | 4 participants | 3 participants | 1 participants |
| Race/Ethnicity, Customized White | 428 participants | 290 participants | 138 participants |
| Sex: Female, Male Female | 187 Participants | 123 Participants | 64 Participants |
| Sex: Female, Male Male | 250 Participants | 173 Participants | 77 Participants |
| Tumor, Node, Metastasis (TNM) Disease Stage Missing | 1 participants | 1 participants | 0 participants |
| Tumor, Node, Metastasis (TNM) Disease Stage Stage IIIB | 34 participants | 22 participants | 12 participants |
| Tumor, Node, Metastasis (TNM) Disease Stage Stage IIIC | 97 participants | 66 participants | 31 participants |
| Tumor, Node, Metastasis (TNM) Disease Stage Stage IV M1a | 119 participants | 76 participants | 43 participants |
| Tumor, Node, Metastasis (TNM) Disease Stage Stage IV M1b | 90 participants | 64 participants | 26 participants |
| Tumor, Node, Metastasis (TNM) Disease Stage Stage IV M1c | 96 participants | 67 participants | 29 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 112 / 127 | 282 / 292 |
| serious Total, serious adverse events | 17 / 127 | 75 / 292 |
Outcome results
Primary
Durable Response Rate
Durable response rate was defined as the percentage of participants with a complete response (CR) or partial response (PR) maintained continuously for at least 6 months from the time the objective response was first observed and initiating within 12 months of starting therapy as assessed by the Endpoint Assessment Committee (EAC). This reflects all new sites of disease as well as disease sites identified at baseline. Disease assessments were performed at the beginning of each treatment cycle in accordance with modified World Health Organization criteria. CR: Disappearance of all clinical evidence of tumor (both measurable and non-measurable but evaluable disease); PR: ≥ 50% reduction in the sum of the products of the perpendicular diameters of all measurable tumors at the time of assessment as compared to baseline.
Time frame: From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months.
Population: Intent-to-treat population (all participants randomized to receive study treatment), excluding one participant who was randomized three times.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GM-CSF | Durable Response Rate | 2.1 percentage of participants |
| Talimogene Laherparepvec | Durable Response Rate | 16.3 percentage of participants |
Comparison: The null hypothesis was that there was no difference in the durable response rate between the talimogene laherparepvec and control arms. Study success was defined as the rejection of this hypothesis such that talimogene laherparepvec was found to be superior to GM-CSF using the 2-sided Fisher's exact test, with a p-value of ≤ 0.0488.p-value: <0.000195% CI: [9.3, 19]Fisher Exact
Secondary
Duration of Response
The duration of response is defined as the longest individual period from entering response (CR or PR as assessed by the EAC) to the first documented evidence of the patient no longer meeting the criteria for being in response or death, whichever is earlier. Responses were censored at the last assessment showing response.
Time frame: From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months.
Population: Participants with an objective response (CR or PR) per EAC assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GM-CSF | Duration of Response | 2.8 months |
| Talimogene Laherparepvec | Duration of Response | NA months |
p-value: 0.086895% CI: [0.14, 1.18]Log Rank
Secondary
Objective Response Rate
Objective response rate was defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) assessed by the Endpoint Assessment Committee (EAC). Best overall response for a patient is the best overall response observed across all time points. Disease assessments were performed at the beginning of each treatment cycle and assessed in accordance with modified World Health Organization criteria. CR: Disappearance of all clinical evidence of tumor (both measurable and non-measurable but evaluable disease); PR: ≥ 50% reduction in the sum of the products of the perpendicular diameters of all measurable tumors at the time of assessment as compared to baseline.
Time frame: From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months.
Population: Intent-to-treat population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GM-CSF | Objective Response Rate | 5.7 percentage of participants |
| Talimogene Laherparepvec | Objective Response Rate | 26.4 percentage of participants |
p-value: <0.000195% CI: [14.4, 27.1]Fisher Exact
Secondary
Overall Survival
Overall survival was defined as the time from the date of randomization to the date of death from any cause. Overall survival time was censored at the last date the patient was known to be alive when the confirmation of death was absent or unknown. Participants were censored at the date of randomization if no additional follow-up data were obtained.
Time frame: From randomization until the first 290 survival events had occurred (data cut-off date of 31 March 2014); median time on follow-up was 44 months.
Population: Intent-to-treat population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GM-CSF | Overall Survival | 18.9 months |
| Talimogene Laherparepvec | Overall Survival | 23.3 months |
Comparison: The primary method for analysis of overall survival was an unadjusted log-rank test. Testing of overall survival was conditional on a statistically significance difference in the primary endpoint of durable response. Success was defined as a p-value ≤ 0.05.p-value: 0.051195% CI: [0.62, 1]Log Rank
Secondary
Response Interval
Response interval is defined as the interval between the date of randomization and the date of the last documented evidence of response (CR or PR as assessed by the Investigator) prior to any new anti-cancer therapy. Response Interval post response onset was censored if a patient was still in response at the last observation.
Time frame: From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months.
Population: Participants with an objective response (CR or PR) per Investigator assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GM-CSF | Response Interval | 7.5 months |
| Talimogene Laherparepvec | Response Interval | NA months |
p-value: 0.00595% CI: [0.13, 0.73]Log Rank
Secondary
Response Onset
Response onset is defined as the time from the date of randomization to the date of the first documented evidence of response (CR or PR) per EAC assessment.
Time frame: From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months.
Population: Participants with an objective response (CR or PR) per EAC assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GM-CSF | Response Onset | 3.7 months |
| Talimogene Laherparepvec | Response Onset | 4.1 months |
p-value: 0.20295% CI: [0.3, 1.3]Log Rank
Secondary
Time to Treatment Failure
Time to treatment failure was assessed by the investigator, and calculated from randomization until the first clinically relevant disease progression where there is no response achieved after the progression, or until death if no such progression occurs. Participants who did not have clinically relevant progression or did not die were censored at the time of the their last tumor assessment. Participants who withdrew from treatment due to a clinically unacceptable toxicity were not considered as an event in the analysis. Progressive disease (PD) is defined as a ≥ 25% increase in the sum of the products of the perpendicular diameters of all measurable tumors since baseline, or the unequivocal appearance of a new tumor since the last response assessment time point. Clinically relevant progressive disease is PD that is associated with a decline in performance status and/or in the opinion of the investigator the patient requires alternative therapy.
Time frame: From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months.
Population: Intent to treat population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GM-CSF | Time to Treatment Failure | 2.9 months |
| Talimogene Laherparepvec | Time to Treatment Failure | 8.2 months |
p-value: <0.000195% CI: [0.32, 0.54]Log Rank